Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase [nitric oxide (NO) synthase] was studied in rat brain both at the light and electron microscopic level with special emphasis on the vascular system. We showed that the cGMP-generating enzyme is located in cells (glial cells and pericytes) surrounding cerebral vessels, but not in the endothelium. For NO synthase, a dual localization was observed. The enzyme is present in parts of the endothelium and in nerve endings apparently innervating larger brain vessels. We propose, therefore, that NO acts on guanylate cyclase both from a "synaptic" and endothelial source.
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PMID:Histochemistry of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase (nitric oxide synthase) in rat brain vasculature. 128 93

1. Nonadrenergic, noncholinergic (NANC) nerves mediate vasodilatation in guinea-pig pulmonary artery (PA) by both endothelium-dependent and endothelium-independent mechanisms. The transmitter(s) involved in the endothelium-independent pathway have not yet been identified. We have therefore investigated the possibility that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) may mediate this neural vasodilator response in guinea-pig branch PA rings denuded of endothelium. 2. Electric field stimulation (EFS, 50 V, 0.2 ms) induced a frequency-dependent (1-24 Hz), tetrodotoxin-sensitive relaxation of the U44069-precontracted PA rings in the presence of adrenergic and cholinergic blockade. 3. The NO synthase inhibitors NG-monomethyl L-arginine (L-NMMA, 100 microM) and NG-nitro L-arginine methyl ester (L-NAME, 30 microM), and the guanylyl cyclase inhibitor methylene blue (5 microM) inhibited the EFS (16 Hz)-induced relaxation by 53 +/- 5, 74 +/- 9 and 82 +/- 9% respectively (n = 5-7, P < 0.01, compared with control rings). 4. Excess concentrations of L-, but not D-arginine (300 microM) completely reversed the inhibitory effect of L-NMMA. 5. The EFS-elicited relaxation (4 Hz) was potentiated by 1 microM zaprinast, a type V phosphodiesterase inhibitor which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP) degradation, but was unaffected by 0.1 microM zardaverine, a type III/IV phosphodiesterase inhibitor which inhibits cyclic AMP degradation. 6. EFS (50 V, 0.2 ms, 16 Hz) induced a 3 fold increase in tissue cyclic GMP content, an action which was inhibited by L-NMMA (100 microM). 7. Pyrogallol (100microM), a superoxide anion generator, also inhibited the EFS-induced relaxation by 53 +/- 9%, and this effect was prevented by superoxide dismutase.8. Chemical sympathetic denervation with 6-hydroxydopamine had no effect on the relaxant response to EFS in the endothelium-denuded PA rings.9. In endothelium-denuded branch PA rings at resting tone, L-NMMA (100 microM) significantly augmented the adrenergic contractile response, an effect which was completely reversed by L-arginine,but not by D-arginine. In the same groups of vessel rings, L-NMMA had no significant effect on the matched contractile response to exogenous noradrenaline.10. These results suggest that NO may be released from intramural nerve endings other than adrenergic nerves (probably NANC nerves), and this leads to vasodilatation via activation of guanylyl cyclase.
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PMID:Role of nitric oxide and guanosine 3',5'-cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea-pig pulmonary arteries. 133 45

Nitric oxide (NO) is an important molecular messenger accounting for endothelial-derived relaxing activity in blood vessels, mediating cytotoxic actions of macrophages, and functioning as a neurotransmitter in the brain and periphery. NO synthase (NOS) from brain has been purified to homogeneity and molecularly cloned. We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS. Activation of PKC in transfected cells reduces NOS enzyme activity by approximately 77% in intact cells and by 50% in protein homogenates from these cells. Utilizing fluorescence spectroscopy we find that purified monomer NOS contains 1 molar equivalent of both FMN and FAD. This stoichiometry is supported by enzymatic digestion of the flavins with phosphodiesterase, and titration of the FMN with a specific FMN binding protein. We demonstrate that purified NOS is labeled by a photoaffinity derivative of calmodulin. These recognition sites on NOS provide multiple means for regulation of NO levels and "cross-talk" between second messenger systems.
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PMID:Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. 137 33

Trehalose dimycolate (TDM), a mycobacterial glycolipid, is a powerful macrophage-priming agent. However, its efficiency seems limited in the case of BALB/c mice. Peritoneal macrophages harvested from TDM-treated BALB/c mice did not control BCG growth in vitro as efficiently as similar macrophages from two other mouse strains, (B6 x D2)F1 and C57BL/6, which are respectively Bcgr and Bcgs. BALB/c macrophages elicited by TDM also exhibited a low capacity to produce hydrogen peroxide and, after activation by lipopolysaccharide (LPS), weak cytostatic activity against P815 mastocytoma cells. Finally, alkaline phosphodiesterase, a marker of resident and inflammatory macrophages, was still expressed at a high level in macrophages of BALB/c mice treated with TDM. Low responsiveness of BALB/c macrophages to stimuli was not observed with TDM only; activation for tumor cytotoxicity of thioglycolate-elicited macrophages from BALB/c mice required also higher doses of interferon-gamma, and LPS. L-Arginine-dependent production of nitric oxide was inducible in macrophages from BALB/c mice, but the conditions required for its induction were more stringent. Thus, the reduced antiproliferative effects of BALB/c macrophages may be due to uncomplete induction of NO synthase after suboptimal stimulation.
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PMID:Low response of BALB/c macrophages to priming and activating signals. 138 43

1. The activation of the L-arginine: nitric oxide (NO) pathway during aggregation of human platelets by adenosine 5'-diphosphate (ADP), arachidonic acid, thrombin and the calcium ionophore A23187 and its inhibition by NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME) and N-iminoethyl-L-ornithine (L-NIO) were studied. The inhibition of the cytosolic platelet NO synthase by these compounds was also examined. 2. Platelet aggregation induced by ADP (1-10 microM) and arachidonic acid (0.1-10 microM), but not that induced by thrombin (1-30 mu ml-1) or A23187 (1-10 nM), was inhibited by L-, but not D-arginine (1-30 microM). However, in the presence of a subthreshold concentration of prostacyclin (0.1 nM) or of M & B 22948 (1 microM), a selective inhibitor of guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterase, L-arginine caused concentration-dependent inhibition of aggregation induced by all of these aggregating agents. 3. L-NMMA, L-NAME and L-NIO (all at 1-30 microM), but not their D-enantiomers, enhanced to the same extent platelet aggregation induced by ADP, arachidonic acid and thrombin without affecting that induced by A23187. 4. In the presence of 300 microM L-arginine, the NO synthase in platelet cytosol was inhibited by L-NMMA, L-NAME and L-NIO with IC50s of 74 +/- 9, 79 +/- 8 and 8.5 +/- 1.5 microM (n = 3), respectively. 5. These results indicate that the L-arginine: NO pathway in human platelets plays a role in the modulation of platelet aggregation.
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PMID:Characterization of the L-arginine:nitric oxide pathway in human platelets. 170 76

The nitric oxide (NO) synthase/cGMP pathway has been studied in vivo in the adult rat hippocampus by monitoring the levels of extracellular cGMP during microdialysis in conscious unrestrained animals. The basal cGMP efflux was concentration-dependently reduced upon local infusion of the NO synthase inhibitor NG-nitro-L-arginine (NARG; 10 microM to 1 mM). The NO donors hydroxylamine and S-nitroso-N-penicillamine, perfused through the dialysis probe at 1 mM, increased by about 200% the extracellular levels of cGMP. The glutamate receptor agonist NMDA (125-500 microM) produced concentration-dependent cGMP responses that were abolished by the selective receptor antagonist D-2-amino-5-phosphonovaleric acid or by NARG. Local perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 1 mM) produced a steady eightfold increase of extracellular cGMP levels. The effect of IBMX was highly sensitive to NARG. The inhibition by NARG of the IBMX-induced cGMP response was reversed when the NO synthase substrate L-arginine was administered. It is concluded that cGMP collected during in vivo microdialysis reflects NO synthase activity in the rat hippocampus. The technique may be utilized to investigate the pathophysiology and the pharmacology of the NO/cGMP pathway in the hippocampus of living animals.
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PMID:Extracellular cGMP in the hippocampus of freely moving rats as an index of nitric oxide (NO) synthase activity. 750 60

1. Treatment of rat mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to induce a macrophage-type of nitric oxide (NO) synthase. Here we report that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is another mediator that triggers induction of NO synthase in mesangial cells. 2. Incubation of mesangial cells with the beta-adrenoceptor agonist, salbutamol, forskolin or cholera toxin, which all activate adenylate cyclase and increase intracellular cyclic AMP concentration, increased nitrite formation in a dose-dependent manner. Likewise, the addition of the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine enhanced NO synthase activity in a dose-dependent manner. 3. There was a lag period of about 8 h before a significantly enhanced secretion of nitrite could be detected upon exposure of cells to forskolin and for maximal stimulation, forskolin had to be present during the whole incubation period. 4. Treatment of mesangial cells with actinomycin D, cycloheximide or dexamethasone completely suppressed forskolin-stimulated NO-synthase activity, thus demonstrating that transcription and protein synthesis are necessary for nitrite formation. 5. Bt2 cyclic AMP, the most potent inducer of nitrite production, increased NO synthase mRNA levels in mesangial cells in a time- and dose-dependent fashion. Dexamethasone completely inhibited the increase of NO synthase mRNA in response to Bt2 cyclic AMP. 6. Combination of Bt2 cyclic AMP and IL-1 beta or TNF alpha revealed a strong synergy in terms of nitrite formation. Time-course studies indicated that cyclic AMP needed to be increased during the whole period of IL-1 Beta stimulation for maximal nitrite production.7. These observations suggest that cyclic AMP controls NO synthase expression in mesangial cells.Furthermore, the signalling cascades triggered by IL-1 Beta and TNF alpha synergize with the cyclic AMP pathway to stimulate NO synthase activity.
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PMID:Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP. 751

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
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PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86

General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
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PMID:Inhibitory effects of anesthetics on cyclic guanosine monophosphate (cGMP) accumulation in rat cerebellar slices. 752 47

Aging is an important risk factor for impotence in men. Because nitric oxide (NO) appears to be the mediator of corpora cavernosal smooth muscle relaxation, we have examined in 5-, 20-, and 30-mo-old rats, designated "adult," "old," and "senescent," respectively, whether aging causes a decrease of erectile response that may correlate with lower NO synthase (NOS) in the penis. Electric field stimulation (EFS) of the cavernosal nerve showed that the maximum intracavernosal pressure (MIP) declined in the old and senescent rats to 80 and 51% of the adult value, respectively. A low systemic dose of the NOS inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME; 2 mg/kg), reduced the MIP by only 38% in the adult rats but decreased it in the old and senescent rats by 72 and 80%, respectively. In the absence of EFS, intracavernosal papaverine (phosphodiesterase inhibitor), or nitroglycerin (NO donor), caused a lower erectile response in the old and senescent rats compared with the adult animals (MIP: 41 and 14%, respectively; duration of the erection 46 and 21%, respectively). Tissue sections from old and senescent penises showed increasing degrees of sclerotic degeneration. In comparison with the adult rats, the penile soluble NOS activity per gram of tissue that is sensitive to L-NAME decreased significantly by 63% in the senescent rats but was elevated in the old rats. These results indicate that aging causes an erectile failure due to factors initially independent from an impairment of penile NO synthesis but which are compounded in the very old rats by the decrease of penile NOS activity.
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PMID:Effect of aging on nitric oxide-mediated penile erection in rats. 753 Sep 24


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